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Extracts preparation
The three crude extracts and 24 fractions were sent to the laboratory of Duke-NUS
Medical School to evaluate their antidengue activity and were prepared by dissolution in
DMSO to obtain solutions at 250 mg/mL.
Cell viability assay
For measurement of compound cytotoxicity, Huh-7 cells were seeded at 2 3 10
4
cells
per well with 10% FBS medium in 96-well white flat-bottom plate. Cells were incubated
for 48 h with various concentrations of compounds tested. Cell viability was measured
using the CellTiterGlo Luminescent cell viability Assay (Promega) kit according to the
manufacturer’s instructions. Luminescence was me asured on a microplate reader (Tecan
Infinite 200 PRO) with a 100 Ms integration time. Cell viability is expressed as the percent-
age of luminescence derived from treated samples relative to that of the untreated control.
Virus infection
Huh-7 cells were seeded in a 24-well plate at 1 3 10
5
cells per well. Three compound
concentrations (200, 100, and 10 μg/mL) were used. For cotreatment, cells were infected
with DENV-2 at a multiplicity of infection (MOI) of 0.3 in the presence of compounds for
1 h. Virus/drug inoculums were removed and a fresh medium containing the indicated
concentrations of compounds was added. For posttreatment, cells were infected with
DENV-2 at a MOI of 0.3 for 1 h. Virus inoculums were removed and a fresh medium con-
taining the indicated concentrations of compounds was added. Cells were incubated for
additional 48 h at 37
C and the supernatants were collected. Virus titers in the superna-
tants were determined by plaque assay using BHK-21 cells. The molecule NITD008 was
used as a positive control for DENV infection (
Yin et al., 2009).
UHPLC-HRMS profiling
All extracts were profiled using a UHPLC-DAD-LTQ Orbitrap XL instrument (Ultimate
3000, Thermo Fisher Scientific, Hemel Hempstead, UK). The UV detection was performed
by a diode array detector (DAD) from 210 to 400 nm. Mass detection was performed using
an electrospray source in positive (PI) and NI modes at 15,000 resolving power [full width
at half maximum (FWHM) at 400 m/z]. The mass scanning range was m/z 1001500 Da.
The capillary temperature was 300
C and voltage was fixed at 4.2 kV (positive mode) and
3.0 kV (negative mode). Mass measurement was externally calibrated before starting the
acquisition. Each full Ms scan was followed by data-dependent Ms/MS on the four most
intense peaks using collision-induced dissociation (35% normalized collision energy, isola-
tion width 2 Da, activation Q of 0.250). The LCMS system was run in binary gradient
mode using a BEH C18 Acquity column (100 3 2.1 mm i.d., 1.7 μm, Waters, MA, USA)
equipped with a guard column. Mobile phase A (MPA) was 0.1% formic acid (FA) in
water and mobile phase B was 0.1% FA in acetonitrile. Gradient conditions were: 0 min,
95% MPA; 0.5 min 95% MPA; 12 min, 5% MPA; 15 min, 5% MPA; 15.5 min, 95% MPA;
19 min, 95% MPA. The flow rate was 0.3 mL/min, column temperature 40
C, and injection
volume 2 μL.
454 13. Antiviral potential of medicinal plants: a case study with guava tree against dengue virus using a metabolomic approach
Medicinal Plants as Anti-infectives
Data processing
The UHPLC-HRMS raw data were converted to abf files (Reifycs Abf Converter) and
processed with Ms-DIAL version 2.56 (
Tsugawa et al., 2015) for mass signal extraction
between 100 and 1500 Da from 0 to 15 min. Respective Ms1 and Ms2 tolerance were set to
0.01 and 0.2 Da in centroid mode. The optimized detection threshold was set to 2.5 3 10
4
for Ms1 and 5 for Ms2. Adducts and complexes were identified to exclude them from the
final peak list. Finally, the peaks were aligned on a QC reference file with a retention time
tolerance of 0.1 min and a mass tolerance of 0.025 Da. The resulting peak list was treated
with MS-CleanR (
Fraisier-Vannier et al., 2020) and then exported to comma-separated
value format prior to MVA using SIMCA-P 1 (version 14.0, Umerics, Umea, Sweden).
Statistical analysis
For multivariate data analysis , all data were log-transformed and Pareto scaled. The
OPLS regression analysis was done with antidengue inhibition values as Y input.
Coefficient scores were used to rank variables according to their DENV-inhibition poten-
tial. For each model, a leave-one-subject-out cross-validation was performed to assess the
model fit. The validity of the discriminant model was verified using permutation tests
(Y-scrambling).
Identification of significant features
Molecular formulae of significant features were calculated with Ms-FINDER 2.12
(
Tsugawa et al., 2016). Various parameters were used in order to reduce the number of
potential candidates, such as the element selection exclusively including C, H, O; mass toler-
ance fixed to Ms1:0.01 Da and Ms2:0.2 Da, and the isotopic ratio tolerance set to 20%. Only
natural product databases focused on plants were selected from UNPD, KNApSAc, PlantCyc,
DNP (CRC Press, v25:2), and CheBI. Compounds from Psidium genus or Myrtaceae family
were prioritized. The results were presented as a list of compounds sorted according to the
score value of the match. This value encompassed uncertainty on accurate mass, the isotopic
pattern score, and the experimental MS/MS fragmentation mirrored to in silico matches. Only
chemical identities were retained with a final score above 5.
Acknowledgments
Chiobouaphong Phakeovilay was supported by Pierre Fabre Foundation and Thomas Vial by IRD. We also thank
Julien Pompon for his collaborative role in the intermediation of the different teams.
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458 13. Antiviral potential of medicinal plants: a case study with guava tree against dengue virus using a metabolomic approach
Medicinal Plants as Anti-infectives
CHAPTER
14
How history can help present research
of new antimicrobial strategies: the
case of cutaneous infections’ remedies
containing metals from the Middle
AgeArabicpharmacopeia
Ve
´
ronique Pitchon
1
, Elora Aubert
2
, Catherine Vonthron
2
and
Pierre Fechter
3
1
CNRS, UMR 7044, Archaeology and Ancient History: Mediterranean - Europe, MISHA,
Strasbourg University, Strasbourg, France
2
CNRS, UMR 7200, Laboratory of Therapeutic
Innovation, Medalis LabEx, Faculty of Pharmacy, Strasbourg University, Strasbourg, France
3
CNRS, UMR 7242, Biotechnology and Cell Signaling, Strasbourg University, Illkirch-
Graffenstaden, France
Introduction
Plants are a valuable source of a wide range of secondary metabolites, which are used
as drugs with different pharmacological activities. Herbal medicine was used extensively
in dermatology for the treatment of acne, wound and burn, viral, fungal, bacterial, para-
sitic infections, dermatitis, psoriasis, vitiligo, alopecia, skin cancer, and other skin
complaints. The medical treatment of skin diseases has the advantage of being able to use
so-called topical drugs, which is to say by direct application to the skin. This allows the use
of products that could prove to be toxic upon ingestion but which by surface application
allows the treatment of infections without necessarily affecting the cells in depth. This is
the case with metals that are widely used in ancient dermatology, although they are rarely
ingested due to their well-known toxicity. This is why we have chosen to do here a review
459
Medicinal Plants as Anti-infectives
DOI:
https://doi.org/10.1016/B978-0-323-90999-0.00016-1 Copyright © 2022 Elsevier Inc. All rights reserved.
of drugs used for the skin, whether they are herbal but contain one or more metals. We
will see that this involves specificities, especially in the preparation because the metal
must be homogeneously dispersed in the medium that receives it and that it does not
affect the active principle of the plants to which it is added. It comments and discusses dif-
ferent surveys of these pharmacopeias, described in
Table 14.1.
Brief history of Arabic medicine
One of the sciences which experienced a peak during the medieval period is that of
pharmacology, which was one of the last to be supplanted by modern science. The use of
this pharmacopeia is still ongoing in the Middle East and India. In the realm of science,
the Arabs are the creators of the real development of pharmacology (
Saad & Said, 2011)
(
Fig. 14.1).
At first, Arab scientists focused on translating Greek medical knowledge. This flourish-
ing civilization in the 8th century CE integrated medicine the humoral theories of
Hippocrates then was interested in the practical aspects of medicine by integrating the
texts of Galen, in particular, the texts of dietetics and, as regards with pharmacology,
enriched the arsenal of Greek plants by integrating the knowledge of Ayurveda and the
TABLE 14.1 List of commented and discussed sources.
Title Author Document
Therapeutic properties of medicinal plants: a
review of their antibacterial activity (part 1)
Al-Snafi A.E. Review & Research, 6(3), (2015),
pp. 1371258
Therapeutic properties of medicinal plants: a
review of their dermatological effects (part 1)
Al-Snafi A.E. International Journal of Pharmacy
Review & Research, 5 (4), (2015),
pp. 328337
The contributions of Arabs physicians in
dermatology
Bachour, H.T. JISHIM, 2, (2002), pp. 4345
On the transmission of Indian medical
texts to the Arabs in the early Middle Ages
Kahl O. Arabica, 66, no. 1 et 2, (2019), pp. 8297
Arabian contributors to dermatology Marquis, L. International Journal of Dermatology
24, (1985), pp. 6064
Dermatologie infectieuse Mokni, M., Dupin N., del
Giuduce P.
Dir. Dan Michael Lipsker - Collection
Dermatologie, Elsevier Masson (2014)
Traditional Arabic medicine in
dermatology
Oumeish Youssef Clinics in Dermatology, 17(1), (1999),
pp. 1320
Medicinal plants for skin and hair care Sharma Laxmikant,
Agarwal Gaurav, Kumar
Ashwani
Indian Journal of Traditional
Knowledge, 2 (1), (2003), pp. 6268
La Parasitologie et la Zoologie dans
l’œuvre d’Avenzoar
The
´
odoride
`
s J. Revue d’histoire des Sciences, 8(2),
(1955), pp. 137145
460 14. The case of cutaneous infections’ remedies
Medicinal Plants as Anti-infectives
Indo-Persian therapeutic arsenal. The 11th century CE, with the Arabic translation of De
materia medica by Dioscorides, marked a real turning point and the work of the Greek bota-
nist has known an unprecedented impact among Arab scientists. It inspired many medie-
val Arabic works in botany and allowed the radical evolution of the Arabic scientific
lexicon. To get around the difficulty of translating Greek botanical terms into Arabic, the
translators will go through Syriac to develop a whole new nomenclature in Arabic.
Principles of Arab medicine: theoretical aspects
Upstream of medical practice through drug or diet treatment, there was a common the-
oretical framework stipulating that the universe is made up of four elements: fire, air,
water, and earth. In this vision, each element has its own quality, of which it is both holder
and producer; humidity for water, heat for fire, dryness for air, and cold for the earth. In
this cosmological conception, the Greek influence appears very clear. One easily finds the
resonance and the influence of the philosophical system of Empedocles, of the theory of
Aristotle, of the treatises of Hippocrates, and of the writings of Galen.
The numerous treatises of pharmacology, drugs, food, and medicinal plants which mul-
tiplied in parallel with the development of Arab-Muslim medicine emphasized the proper-
ties of drugs and their qualities. There are thus descriptions of preparations of medicinal
products based on plants, animal, or mineral matter incorporating data concerning the
qualities of each component with the mention of mixing them, as appropriate, with fresh,
cold, lukewarm water, or rainwater.
The disturbance of the balance of the humors and the return to the state of equilibrium
meaning healing was treated by the addition of heat during an overproduction of cold or
by a humidifying recipe when it comes to balance an excess of drought. The treatments
FIGURE 14.1 14th century Arabic pharmacy.
461Brief history of Arabic medicine
Medicinal Plants as Anti-infectives
also took into account the influence of the climate, the seasons, the age, the nature of the organ
to be treated, the disease, and the patient’s temperament. These four Aristotelian categories
(quality, quantity, time, and manner) formed the framework of this medical discourse.
Arab sources of pharmacology: the aqr
¯
ab
¯
adh¯ın, a constituted literature
Muslims were excellent organizers of knowledge and this ability to organize led to the
production of forms of texts specially dedicated to pharmacology. These forms of text can
be placed in more or less precise categories which generally indicate the main directions
of research and thinking and to place our reflection over a long period of time, we have
studied a wide range of sources written between the 9th and 13th centuries.
There are many sources relating to pharmacology because indeed every medieval Arab
doctor left a trace not only of the theoretical aspects of medicine but of its practical aspects
by writing pharmacopeias that list several thousand drugs.
The Arab-Muslims developed texts on the basis of the Greek classification but also generated
major new types of pharmacological literary models. Their approach was not only enumerative
but much more flexible. In the pharmacological literature a number of subjects flourished
exploring new horizons of knowledge, resulting in new understanding and new areas to invest.
The texts of Arabic pharmacology can be divided into two categories, that relating
directly to the subject and that having a more or less distant relation with this same sub-
ject. For example, for this second category, we find works on how to cure during travel or
on the hisba, which is the common law regulating more particularly medicine and phar-
macy, medical biographies as well as works on botany, zoology, which can also shed light
on pharmacology; one finds in these texts scattered but nevertheless, useful information.
However, the knowledge produced existed in the form of purely pharmacological texts
and meticulously followed all possible educational directions. As a result, these texts
belong to perfectly delimited groups which can be placed in the following categories:
• medical formularies (aqr ¯ab ¯adh
¯
ın)
• books on poisons
• lists of synonyms in alphabetical order
• tables, synoptic treatises
• alphabetical lists of plants, minerals (book of simples)
• chapters of medical treatises
• methods to check purity of drugs
• special books on particular diseases (eyes, sexual organs, pulse, etc.)
In general, these works contain more or less descriptive information on the diseases,
symptoms, drugs and procedure, and sometimes dosage and form of the drug. There is no
systematization of the written form but in general, the works are divided into chapters,
relating either to the nature of the diseases affecting an organ or to the forms taken by the
drug (pill, sirup, ointment, cataplas m). While some authors have opted for a classification
in tables with an alphabetical arrangement, others give a set of generalities on the nature
of the diseases and their links with the theory of humors before proposing a set of medical
preparations useful for the care of a disease or a type of diseases (
Table 14.2).
462 14. The case of cutaneous infections’ remedies
Medicinal Plants as Anti-infectives
Cutaneous infections and medications
The specificity of skin and eye diseases in the pharmacopeias and the nature of
the diseases treated
Dermatological diseases have been particularly well understood by Arab doctors
because the skin constitutes a particular element of the human body. Visible to everyone,
human skin, the outer covering of the body, is the largest organ in the body. It is also its
first line of defense. The skin is the most superficial and most visible organ. Very early on,
it offered to doctors the possibility of observations, some of which are still relevant.
The skin is a complex organ of the human body. Its surface extends for approximately
2m
2
; it weighs approximately 3 kg for an adult with a total weight of 70 kg: it already
TABLE 14.2 List of sources used (913th centuries CE).
Title Author Pe
´
riod Document
Geographical
zone
Kit¯ab jaw ¯ahit al-
t
˙
ib al mufrada Yuh
˙
an
¯
a ibn
M
¯
asawaih
9th
CE
Books of
simple
Baghdad
Al-aqr¯ab¯adh
¯
ın S
¯
abur ibn Sahl 9th
CE
Medical
formularies
Baghdad
Al-aqr¯ab¯adh
¯
ın Al-Kind
¯
ı 9th
CE
Medical
formularies
Baghdad
Kit¯ab al-sum
¯
um Ibn Wahsh
¯
ıya 10th
CE
Books on
poisons
Kufa
Q¯an
¯
un f
¯
ı al-t
˙
ibb Ibn S
¯
ına XI s. Medical
treatise
Persia
Al-aqr¯ab¯adh
¯
ın Ibn al-Tilm
¯
ıdh 12th
CE
Medical
formularies
Baghdad
Taysi
¯
rfi
¯
’l-muda¯wa¯t wa’l-tadbi
¯
r Ibn Zuhr 12th
CE
Medical
treatise
Al-Andalus
Kitab al-Musta’ni Ibn Bikl
¯
arish 12th
CE
Synoptic table Al-Andalus
Shar’ asm ¯a’ al-uqq ¯ar Maı
¨
monides 12th
CE
Glossary Al-Andalus/
Cairo
Kit¯ab al-qar ¯ab¯adh
¯
ın ala tart
¯
ıb al-ilal al-Samarqand
¯
ı 13th
CE
Medical
formularies
Baghdad
Kit¯ab al-gh ¯ami li mufrad¯at al adawiga wa al a
˙
gd
˙
iya Ibn Baytar 13th
CE
Book of
simples
Al-Andalus/
Damas
Minh¯aj al-dukk ¯an wa-dustur al-a’yan f
¯
ı a’m ¯al wa-tar¯ak
¯
ıb
al-adwiya al-n ¯afi’a lil-ins¯an
al-K
¯
uh
¯
ın al-’At
˙
t
˙
¯
ar
al-Isr
¯
a’
¯
ıl
¯
ı
13th
CE
Manual of
pharmacy
Cairo
463Cutaneous infections and medications
Medicinal Plants as Anti-infectives